The role of immune dysfunction in the pathophysiology of autism.

1Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA.

Abstract

Autism spectrum disorders (ASD) are a complex group of neurodevelopmental disorders encompassing impairments in communication, social interactions and restricted stereotypical behaviors. Although a link between altered immune responses and ASD was first recognized nearly 40 years ago, only recently has new evidence started to shed light on the complex multifaceted relationship between immune dysfunction and behavior in ASD. Neurobiological research in ASD has highlighted pathways involved in neural development, synapse plasticity, structural brain abnormalities, cognition and behavior. At the same time, several lines of evidence point to altered immune dysfunction in ASD that directly impacts some or all these neurological processes. Extensive alterations in immune function have now been described in both children and adults with ASD, including ongoing inflammation in brain specimens, elevated pro-inflammatory cytokine profiles in the CSF and blood, increased presence of brain-specific auto-antibodies and altered immune cell function. Furthermore, these dysfunctional immune responses are associated with increased impairments in behaviors characteristic of core features of ASD, in particular, deficits in social interactions and communication. This accumulating evidence suggests that immune processes play a key role in the pathophysiology of ASD. This review will discuss the current state of our knowledge of immune dysfunction in ASD, how these findings may impact on underlying neuro-immune mechanisms and implicate potential areas where the manipulation of the immune response could have an impact on behavior and immunity in ASD.

Immune dysfunction in ASD involves a network of interactions between several cell types, from the innate and adaptive arms of the immune system. The CNS is selective but several immune factors mediate profound effects of CNS function. Increased cytokine production, such TNF-α and IL-1β inhibit neurogenesis and promote neuron death, while IL-6 may promote the growth and proliferation of neurons and oligodendrocytes. Increased levels of complement proteins can participate in synaptic scaling, opsonizing synapses and targeting them for removal by phagocytic microglia. Activated microglia may additionally mediate synaptic pruning via MHCI interactions. Collectively this immune dysfunction in ASD can exert several negative effects on behavior, including impaired cognitive function, and social withdrawal as well as aberrant behavior observed in ASD.